Alternative titles; symbols
HGNC Approved Gene Symbol: LMBR1
SNOMEDCT: 177504007, 715440003, 719158007, 719950001;
Cytogenetic location: 7q36.3 Genomic coordinates (GRCh38) : 7:156,669,012-156,893,183 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.3 | Acheiropody | 200500 | Autosomal recessive | 3 |
| Laurin-Sandrow syndrome | 135750 | Autosomal dominant | 3 | |
| Syndactyly, type IV | 186200 | Autosomal dominant | 3 | |
| Triphalangeal thumb-polysyndactyly syndrome | 190605 | Autosomal dominant | 3 |
LMBR1 is a transmembrane protein predicted to function as a receptor (Ianakiev et al., 2001).
Physical and transcriptional mapping of the 7q36 region by Heus et al. (1999) identified 3 transcripts, one of which, designated C7orf2 (LMBR1), is the human ortholog of the mouse Lmbr1 gene and encodes a putative receptor. Clark et al. (2000) cloned the LMBR1 cDNA, which encodes a deduced 490-amino acid protein containing 9 putative transmembrane domains and a coiled-coil domain. The protein shares 95% sequence identity with the mouse Lmbr1 protein. Ianakiev et al. (2001) noted that LMBR1 is ubiquitously expressed.
Clark et al. (2000) determined that the LMBR1 gene contains 17 exons and spans approximately 200 kb of genomic DNA.
Intron 5 of the LMBR1 gene contains the zone of polarizing activity (ZPA) regulatory sequence (ZRS; 620738), a cis regulatory element for the SHH gene (600725) involved in limb and digit development.
The LMBR1 gene maps to chromosome 7q36 (Ianakiev et al., 2001).
Acheiropody
Clark et al. (2000) found that Lmbr1 expression altered the developing limbs of Hemimelic extra toes (Hx) mice. The Hx mutation causes hemimelia of the radius and tibia and preaxial polydactyly on both forelimbs and hindlimbs (Knudsen and Kochhar, 1981). Ianakiev et al. (2001) proposed that the genomic location of the LMBR1 gene, as well as the phenotype of Hx mice, make LMBR1 a good candidate for acheiropody (200500), a disorder characterized by bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet that had been mapped by linkage analysis to chromosome 7q36 by Escamilla et al. (2000).
Ianakiev et al. (2001) narrowed the critical region for acheiropody (200500) on chromosome 7q36 and subsequently identified a mutation in the LMBR1 gene in all 5 unrelated Brazilian families with acheiropody studied. A genomic 4- to 6-kb deletion led to a transcript lacking exon 4 and introducing a premature stop codon downstream of exon 3 (605522.0001). Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all cases in Brazil.
Triphalangeal Thumb with Polysyndactyly or Syndactyly Type IV
In a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly mapping to chromosome 7q36 (TPTPS; 190605), Klopocki et al. (2008) did not find any point mutations in the LMBR1 gene, but array CGH analysis identified a heterozygous 589-kb duplication comprising the ZRS region (605522.0009). The authors noted that the phenotype was similar to that caused by point mutations in the ZRS.
In 6 Han Chinese families with TPTPS and/or syndactyly type IV (SDTY4; 186200), Sun et al. (2008) identified heterozygous duplications involving the ZRS, ranging from 131 kb to 398 kb (see, e.g., 605522.0006 and 605522.0010). Using quantitative PCR assays, the authors defined a common overlapping segment of 32,757 bp, which contains the ZRS enhancer. The duplications cosegregated with the limb phenotype in all 6 families and were not found in unaffected family members or in 50 unrelated Han Chinese controls. One of the families with TPTPS had previously been studied by Wang et al. (2007) and found to have a point mutation in intron 5 of the LMBR1 gene (see 605522.0006); Sun et al. (2008) suggested that the point mutation may represent a rare polymorphism.
In a Chinese family with type IV syndactyly (SDTY4; 186200), previously studied by Sato et al. (2007), Wu et al. (2009) performed quantitative PCR and detected a ZRS duplication involving at least 105 kb that segregated with the limb phenotype in the family and was not found in 50 unrelated ethnically matched controls. Copy number and loss-of-heterozygosity analyses confirmed that the duplication spanned a 97-kb segment (nucleotides 156,240,230-156,336,835) including the LMBR1 gene. Breakpoint analysis identified a duplication of between 105 to 115 kb (centromeric breakpoint between nucleotides 156,230,391-156,232,366 and telomeric breakpoint between nucleotides 156,337,864-156,345,168). Wu et al. (2009) noted that of 8 reported families with duplications involving ZRS, the present family, with the smallest duplication, had the most severe lower limb malformations, suggesting that a critical region for the disorder might be located within that duplication. Two affected members of the family also had tibial hypoplasia, and Wu et al. (2009) concluded that SDTY4 with tibial hypoplasia is a severe clinical subtype of SDTY4.
In patients with limb anomalies, Wieczorek et al. (2010) identified 2 microduplications involving the ZRS region and the LMBR1 gene: in a patient with SDTY4, they identified an approximately 73-kb duplication (605522.0016), and in a Turkish family with triphalangeal thumb-polysyndactyly syndrome (TPTPS), they identified a 276-kb duplication. The authors stated that because of the complex and repetitive nature of this genomic region, they were unable to determine the exact orientation of the duplications. They proposed the term 'ZRS-associated syndromes' for the various limb malformations caused by alterations of the ZRS in the LMBR1 gene.
Laurin-Sandrow Syndrome
In 2 families with syndactyly type IV and 3 with Laurin-Sandrow syndrome (LSS; 135750), Lohan et al. (2014) screened for copy number variation in the 7q36 chromosomal region and detected heterozygosity for 5 different microduplications of the ZRS region in intron 5 of the LMBR1 gene. The 2 longer duplications, at approximately 255 kb and 179 kb, respectively, were present in affected members of the 2 families with SDTY4, whereas the shorter mutations, ranging from 16 to 75 kb (605522.0018-605522.0020), were present in the patients with LSS. Lohan et al. (2014) suggested that smaller duplications in the ZRS region of LMBR1 are associated with a more severe phenotype.
In affected individuals from 5 unrelated families with acheiropody (ACHP; 200500) in Brazil, Ianakiev et al. (2001) identified a homozygous 4- to 6-kb deletion in the LMBR1 gene. The mutation leads to the production of an LMBR1 transcript that lacks exon 4 and introduces a frameshift leading to a premature stop codon downstream of exon 3. The boundaries of the deletion appeared to be 1.2 to 2.5 kb 5-prime of exon 4 and 2.7 to 3.5 kb 3-prime of exon 4. Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all cases in Brazil. The approximately 1.3 cM of the 7q36 region shared in all 5 families suggested a relatively recent age (31 generations) for this common mutation.
In affected members of a Han Chinese family (family 6) with triphalangeal thumb-polysyndactyly syndrome (TPTPS; 190605), Sun et al. (2008) identified heterozygosity for a 398-kb discontinuous duplication in intron 5 of the LMBR1 gene, containing the ZRS enhancer. A deletion polymorphism in the normal LMBR1 allele was excluded by qPCR assays in different affected individuals of the same family. The duplication was not found in unaffected family members or in 50 unrelated Han Chinese controls. This family had been previously studied by Wang et al. (2007), who identified a 4220C-T transition in intron 5 of the LMBR1 gene in 17 affected members and 1 unaffected member of the family; Sun et al. (2008) suggested that the single-base substitution, which occurred outside the ZRS region, might represent a rare polymorphism.
In 9 affected members of a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly (TPTPS; 190605), Klopocki et al. (2008) identified heterozygosity for a 589-kb duplication involving intron 5 of the LMBR1 gene and comprising the ZRS. By direct sequencing, the microduplication was found to extend from nucleotide 155,836,147 to nucleotide 156,424,965, with the telomeric breakpoint located upstream of LMBR1. The duplication was not found in 6 clinically unaffected family members. The authors stated that the duplication was most likely causative since deletions/duplications in this genomic region or of the BAC clones used had not been observed in more than 700 individuals and were not described as a DNA copy number variant in the genomic variants database.
In a Han Chinese mother and daughter with type IV syndactyly (SDTY4; 186200), Sun et al. (2008) identified heterozygosity for a 235-kb duplication involving intron 5 of the LMBR1 gene and including the ZRS. The duplication was not found in unaffected family members or in 50 unrelated Han Chinese controls.
In a female patient (family 3) with complete cutaneous syndactyly and hexadactyly of both hands (SDTY4; 186200), who was originally reported by Gillessen-Kaesbach and Majewski (1991), Wieczorek et al. (2010) identified a heterozygous 73-kb duplication involving part of the LMBR1 gene, including the ZRS region. They designated the duplication arr7q36.3(156,265,512x2,156,265,453-156,354,638x3,156,354,579x2), but noted that because of the complex and repetitive nature of this genomic region, they were unable to determine the exact orientation of the duplication.
In a father and son (family 5) with bilateral complete syndactyly of the hands, preaxial mirror-image polysyndactyly of the feet, absent tibia, and duplication of the fibula (LSS; 135750), who were originally reported by Kjaer et al. (2005), Lohan et al. (2014) identified heterozygosity for a 16-kb duplication in the ZRS region in intron 5 of the LMBR1 gene (chr7:156,578,108-156,594,751, GRCh37). Additional features in the patients included hypoplastic alae nasi and patellar aplasia.
In a Pakistani father and 2 daughters (family 4) with cup-shaped polysyndactyly of the hands and mirror-image polysyndactyly of the feet (LSS; 135750), Lohan et al. (2014) identified heterozygosity for an approximately 47-kb duplication in the ZRS region in intron 5 of the LMBR1 gene (chr7:156,563,856-156,610,632, GRCh37).
In an Indian boy (family 3) with bilateral polysyndactyly of the hands, mirror-image polysyndactyly of the feet, absent tibia, and duplication of the fibula (LSS; 135750), Lohan et al. (2014) identified heterozygosity for an approximately 75-kb duplication involving the ZRS region in intron 5 as well as several exons of the LMBR1 gene (chr7:156,570,780-156,646,750, GRCh37). The patient, who was originally described by Patil and Bhat (2013), also exhibited mild facial dysmorphism, with underdeveloped alae nasi, broad nasal tip, and short grooved columella.
Clark, R. M., Marker, P. C., Kingsley, D. M. A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of hemimelic extra-toes mutant mice. Genomics 67: 19-27, 2000. [PubMed: 10945466] [Full Text: https://doi.org/10.1006/geno.2000.6225]
Escamilla, M. A., DeMille, M. C., Benavides, E., Roche, E., Almasy, L., Pittman, S., Hauser, J., Lew, D. F., Freimer, N. B., Whittle, M. R. A minimalist approach to gene mapping: locating the gene for acheiropodia, by homozygosity analysis. Am. J. Hum. Genet. 66: 1995-2000, 2000. [PubMed: 10780921] [Full Text: https://doi.org/10.1086/302921]
Gillessen-Kaesbach, G., Majewski, F. Bilateral complete polysyndactyly (type IV Haas). Am. J. Med. Genet. 38: 29-31, 1991. [PubMed: 1849351] [Full Text: https://doi.org/10.1002/ajmg.1320380108]
Heus, H. C., Hing, A., van Baren, M. J., Joosse, M., Breedveld, G. J., Wang, J. C., Burgess, A., Donnis-Keller, H., Berglund, C., Zguricas, J., Scherer, S. W., Rommens, J. M., Oostra, B. A., Heutink, P. A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36. Genomics 57: 342-351, 1999. [PubMed: 10329000] [Full Text: https://doi.org/10.1006/geno.1999.5796]
Ianakiev, P., van Baren, M. J., Daly, M. J., Toledo, S. P. A., Cavalcanti, M. G., Neto, J. C., Silveira, E. L., Freire-Maia, A., Heutink, P., Kilpatrick, M. W., Tsipouras, P. Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene. Am. J. Hum. Genet. 68: 38-45, 2001. [PubMed: 11090342] [Full Text: https://doi.org/10.1086/316955]
Kjaer, K. W., Hansen, L., Eiberg, H., Christensen, K. S., Opitz, J. M., Tommerup, N. Male-to-male transmission in Laurin-Sandrow syndrome and exclusion of RARB and RARG. Am. J. Med. Genet. 137A: 148-152, 2005. [PubMed: 16059937] [Full Text: https://doi.org/10.1002/ajmg.a.30820]
Klopocki, E., Ott, C.-E., Benatar, N., Ullmann, R., Mundlos, S., Lehmann, K. A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J. Med. Genet. 45: 370-375, 2008. [PubMed: 18178630] [Full Text: https://doi.org/10.1136/jmg.2007.055699]
Knudsen, T. B., Kochhar, D. M. The role of morphogenetic cell death during abnormal limb-bud outgrowth in mice heterozygous for the dominant mutation hemimelia-extra toe (Hmx). J. Embryol. Exp. Morphol. 65 (suppl.): 289-307, 1981. [PubMed: 7334311]
Lohan, S., Spielmann, M., Doelken, S. C., Flottmann, R., Muhammad, F., Baig, S. M., Wajid, M., Hulsemann, W., Habenicht, R., Kjaer, K. W., Patil, S. J., Girisha, K. M., Abarca-Barriga, H. H., Mundlos, S., Klopocki, E. Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome. Clin. Genet. 86: 318-325, 2014. [PubMed: 24456159] [Full Text: https://doi.org/10.1111/cge.12352]
Patil, S. J., Bhat, V. Laurin-Sandrow syndrome: a case report. Newsl. Indian Acad. Med. Genet. 6: 3-5, 2013.
Sato, D., Liang, D., Wu, L., Pan, Q., Xia, K., Dai, H., Wang, H., Nishimura, G., Yoshiura, K.-I., Xia, J., Niikawa, N. A syndactyly type IV locus maps to 7q36. J. Hum. Genet. 52: 561-564, 2007. [PubMed: 17476456] [Full Text: https://doi.org/10.1007/s10038-007-0150-5]
Sun, M., Ma, F., Zeng, X., Liu, Q., Zhao, X.-L., Wu, F.-X., Wu, G.-P., Zhang, Z.-F., Gu, B., Zhao, Y.-F., Tian, S.-H., Lin, B., Kong, X.-Y., Zhang, X.-L., Yang, W., Lo, W. H.-Y., Zhang, X. Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer. J. Med. Genet. 45: 589-595, 2008. [PubMed: 18417549] [Full Text: https://doi.org/10.1136/jmg.2008.057646]
Wang, Z.-Q., Tian, S.-H., Shi, Y.-Z., Zhou, P.-T., Wang, Z.-Y., Shu, R.-Z., Hu, L., Kong, X. A single C to T transition in intron 5 of LMBR1 gene is associated with triphalangeal thumb-polysyndactyly syndrome in a Chinese family. Biochem. Biophys. Res. Commun. 355: 312-317, 2007. [PubMed: 17300748] [Full Text: https://doi.org/10.1016/j.bbrc.2007.01.129]
Wieczorek, D., Pawlik, B., Li, Y., Akarsu, N. A., Caliebe, A., May, K. J. W., Schweiger, B., Vargas, F. R., Balci, S., Gillessen-Kaesbach, G., Wollnik, B. A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb. Hum. Mutat. 31: 81-89, 2010. [PubMed: 19847792] [Full Text: https://doi.org/10.1002/humu.21142]
Wu, L., Liang, D., Niikawa, N., Ma, F., Sun, M., Pan, Q., Long, Z., Zhou, Z., Yoshiura, K., Wang, H., Sato, D., Nishimura, G., Dai, H., Zhang, X., Xia, J. A ZRS duplication causes syndactyly type IV with tibial hypoplasia. (Letter) Am. J. Med. Genet. 149A: 816-818, 2009. [PubMed: 19291772] [Full Text: https://doi.org/10.1002/ajmg.a.32740]